Fuks Francois, Hurd Paul J, Wolf Daniel, Nan Xinsheng, Bird Adrian P, Kouzarides Tony
Wellcome/Cancer Research UK Institute and Department of Pathology, University of Cambridge, Tennis Court Road, United Kingdom.
J Biol Chem. 2003 Feb 7;278(6):4035-40. doi: 10.1074/jbc.M210256200. Epub 2002 Nov 9.
DNA methylation plays an important role in mammalian development and correlates with chromatin-associated gene silencing. The recruitment of MeCP2 to methylated CpG dinucleotides represents a major mechanism by which DNA methylation can repress transcription. MeCP2 silences gene expression partly by recruiting histone deacetylase (HDAC) activity, resulting in chromatin remodeling. Here, we show that MeCP2 associates with histone methyltransferase activity in vivo and that this activity is directed against Lys(9) of histone H3. Two characterized repression domains of MeCP2 are involved in tethering the histone methyltransferase to MeCP2. We asked if MeCP2 can deliver Lys(9) H3 methylation to the H19 gene, whose activity it represses. We show that the presence of MeCP2 on nucleosomes within the repressor region of the H19 gene (the differentially methylated domain) coincides with an increase in H3 Lys(9) methylation. Our data provide evidence that MeCP2 reinforces a repressive chromatin state by acting as a bridge between two global epigenetic modifications, DNA methylation and histone methylation.
DNA甲基化在哺乳动物发育中起重要作用，并与染色质相关的基因沉默相关。MeCP2被招募到甲基化的CpG二核苷酸上代表了DNA甲基化抑制转录的一种主要机制。MeCP2部分通过招募组蛋白去乙酰化酶（HDAC）活性使基因表达沉默，导致染色质重塑。在此，我们表明MeCP2在体内与组蛋白甲基转移酶活性相关联，并且这种活性针对组蛋白H3的赖氨酸（9）。MeCP2的两个已表征的抑制结构域参与将组蛋白甲基转移酶与MeCP2拴系在一起。我们询问MeCP2是否能将H3赖氨酸（9）甲基化传递到其活性受到抑制的H19基因。我们表明，在H19基因的抑制区域（差异甲基化区域）内的核小体上存在MeCP2与H3赖氨酸（9）甲基化的增加相吻合。我们的数据提供了证据，表明MeCP2通过作为两种全局表观遗传修饰（DNA甲基化和组蛋白甲基化）之间的桥梁来加强抑制性染色质状态。
